The proarrhythmic effects of hypothermia in atria isolated from 5-HT 4 -receptor-overexpressing mice.

We investigated whether hypothermia would be arrhythmogenic in mice that overexpress the human 5-HT ₄ receptor only in their cardiac myocytes (5-HT ₄ -TG). Contractile studies were performed in isolated, electrically driven (1 Hz) left and spontaneously beating right atrial preparations of 5-HT ₄ -TG and littermate wild-type control mice (WT). Hypothermia (23 °C) decreased the force of contraction in the mouse right and left atrial preparations. Moreover, the concentration-dependent positive inotropic effects of 5-HT were blunted but still shifted to lower 5-HT concentrations in the left 5-HT ₄ -TG atria in hypothermia compared to normothermia (37 °C). Furthermore, hypothermia increased the incidence of right atrial arrhythmias in 5-HT ₄ -TG more than in WT mice. In contrast, at 37 °C, lowering the potassium concentration from 5.2 to 2.0 mM also induced arrhythmias in the right atrium, but with a similar incidence in WT and 5-HT ₄ -TG mice. In contrast, 10 μM d,l-sotalol and 300 μM erythromycin did not induce arrhythmias. Hypothermia was accompanied by the increased expression of heat shock protein 70 (HSP70) in WT but not in 5-HT ₄ -TG mice. We concluded that without the stimulation of 5-HT ₄ -receptors by exogenous agonists, a simple temperature reduction can increase arrhythmias in 5-HT ₄ -TG mice. It is tempting to speculate that in human patients, 5-HT ₄ receptors might contribute to potentially deadly hypothermia-induced arrhythmias.
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